Aging and immunity to infections. Infectious diseases, such as influenza, lead to high morbidity and mortality in elderly populations. In addition, the efficacy of vaccines is also significantly reduced for elderly populations, leaving them much more vulnerable to infection. While it is well known that the adaptive immune response to influenza infection and immunization declines with aging, the impact of specific age-related changes in T cell function remain to elucidated. Defining the underlying defects in the immune response with aging in human populations is extremely difficult. Fortunately, mouse models allow us to precisely examine age-related changes in the immune system and determine the effect of these changes on a response to a particular pathogen. Thus, the key focus of this program is to assess the development of age-related changes in T cell function and how these contribute to reduced immunity. The projects in this program take advantage of sophisticated mouse models to identify age-related defects in adaptive immunity and to analyze the impact of these defects, the mechanisms involved in these defects and whether they can be overcome. Project 1 "Impact of aging on CD4 immunity to flu" will examine the impact of age on the initial priming and subsequent generation of CD4 T cells and if this can be enhanced. Project 2 "Enhancing aged CD4 cognate function with cytokines" will focus on examining the role of age-related changes in CD4 T cell cognate helper function and how this impacts the production of protective antibodies following vaccination. Project 3 "Impact of age on CDS T cell immunity to influenza" will examine CDS T cell memory generation and function, which is dramatically reduced with aging possibly due to changes in homeostasis of memory T cell subsets. Project 4 "Impact of aging on the T cell repertoire and cellular immunity to influenza virus" will examine age-related changes in CD4 and CDS T cell repertoire and how these influence the ability to respond to influenza infection. The knowledge generated will allow the future development of strategies to overcome these defects and enhance vaccine efficacy for the elderly.